Asthma is a prevalent chronic respiratory condition. Most patients can manage their symptoms with standard treatments but approximately 5-10% experience severe uncontrolled asthma (SUA), characterized by persistent symptoms and frequent exacerbations despite optimized therapy. This retrospective, observational, multicentre study conducted in southern Spain aimed to evaluate the effectiveness of benralizumab in patients with SUA and identify predictive markers of response. A total of 99 patients were selected. Mean age of participants was 63 ± 15.3 years. Results showed that 79.8% of patients achieved a 50% reduction in oral corticosteroid (OCS) use, 81.8% experienced at least a 50% reduction in exacerbations, and 75.7% had a ≥ 10% improvement or maintained %forced expiratory volume in 1 s (FEV) above 80%. Significant improvements were observed in lung function, asthma control, and a reduction in eosinophil levels (p < 0.001). The frequency of exacerbations and OCS cycles significantly decreased (p < 0.001), and ACT scores improved. The presence of concomitant COPD was associated with a lower probability of lung function improvement, highlighting the importance of phenotypic characterization in treatment response. Importantly, higher baseline eosinophil counts were associated with better clinical outcomes, suggesting their potential as predictive biomarkers. This study supports the real-world effectiveness of benralizumab in reducing OCS dependency, exacerbations, and enhancing pulmonary function in patients with severe uncontrolled asthma.